Extensive studies have established the association and linkage between HLA and IDDM. These studies have confirmed the positive associations with B8, B15, B40, B18, DR3, and DR4, with negative associations with B7 and DR2. In addition, we have confirmed the findings of significant associations with specific haplotypes found in IDDM patients more frequent than in normal controls. The identification of five high-risk haplotypes in our sample (determined by HLA-B, Bf, and HLA-DR), including the rare B8-BfS-DR4 haplotype, still did not resolve the heterogeneity question. In past studies, the high-risk haplotype B8-DR3 was considered to be an "autoimmune" HLA haplotype, as it occurs not only in high frequency in IDDM but also in other autoimmune diseases, such as SLE, Graves' disease, Addison's disease, and others. To date, genetic epidemiology has not been applied to autoimmune disease with the background of IDDM. Genetic analysis of 150 families with IDDM without other autoimmune disease versus 70 families with IDDM and other autoimmune disease will be applied in HLA typed, highly characterized families. It is postulated that the application of heterogeneity tests of linkage and model fitting with the program COMBIN will allow the evaluation of evidence of a different etiology of IDDM with and without other autoimmune disease. Data leading us to the conclusion of heterogeneity based on a common "autoimmune HLA haplotype" would provide significant leads in the common genetic basis of autoimmune disease.